Neuropathological studies of brains from patients with Alzheimer's disease (AD) have led to the hypothesis that the olfactory system is the initial site of involvement of the Alzheimer's disease process. In contrast to the auditory, visual, somatosensory, and motor pathways, significant numbers of neurofibrillary tangles are found in the olfactory pathways of AD brains, particularly regions receiving direct projections from the olfactory bulb, including the uncus the medial amygdaloid nuclei, and the prepyriform, pyriform, and entorhinal cortices. . Such observations, along with recent data demonstrating (a) olfactory dysfunction in many AD patients and (b) transport of viruses and other substances from the nasal cavity into the brain via the olfactory fila, suggest that substances etiologically associated with AD may be transported from the nasal cavity directly into the brain by the primary olfactory neurons. Parkinson's disease (PD) is also accompanied by odor identification and detection deficits similar to those observed in AD. However, neuropathological studies of PD olfactory pathways analogous to those performed on AD pathways have not been made. Furthermore, past studies of olfactory function in PD, as well as in AD, were performed mainly on patients who have been symptomatic for over a year and only a few types of olfactory tests were administered. Clearly, very early comprehensive testing is needed to establish the nature and time of onset of the olfactory disorders associated with AD and PD, as well as possible differences between them. Comprehensive longitudinal of factory testing of very early AD and PD patients will be performed in Experiment 1 to address these needs. The test results from the AD and PD patient groups will be compared to one another and to those from an age-, gender-, and race-matched normal control group. It will be determined whether the test scores correlate with levels of selected neurotransmitter metabolites obtained from a sample of lumbar CSF, as well as with basic neuropsychological measures of cognitive function. Experiment 2 will focus on relatively old AD and PD patients with, at most, mild dementia (to allow valid ante-mortem sensory testing). Relationships will be determined between (a) ante-mortem neuropsychological, behavioral, and sensory measures and (b) post-mortem neuropathological and neurochemical measures, including levels of serotonin, norepinephrine, dopamine, somatostatin, and acetylcholine present in selected brain regions. Close attention will be paid to the topographic distribution and degree of morphological and/or neurotransmitter alterations in different parts of the brain, with an em- phasis on olfactory-related structures. This research will yield basic information about the olfactory dysfunction that accompanies AD and PD and how these alterations relate to anatomical and neurochemical changes associated